|
| A) | Substances controlled by international drug conventions | ||
| B) | Substances of abuse not controlled by drug conventions that may pose a public health threat | ||
| C) | Newly invented psychoactive drugs | ||
| D) | Psychoactive substances that have re-emerged after being banned |
A unique trend in recreational and problematic drug use began to emerge in the United States around 2008, with the introduction and proliferation of previously unknown or unavailable psychoactive substances. By 2015, this trend became an established element of domestic and global recreational drug cultures, and nearly two decades later is the center of a global drug crisis. The United Nations Office for Drug and Crime (UNODC) defines novel or new psychoactive substances (NPS) as "a substance of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat" [1]. The use of the word "new" or "novel" does not necessarily refer to the invention of a new drug, but rather indicates a substance has emerged or re-emerged as a psychoactive substance or synthetic drug of abuse. NPS often have similar molecular structures as controlled or banned substances but are slightly modified by manufacturing and/or trafficking organizations with intent to circumvent existing drug laws [1,12].
| A) | Increased MDMA purity and availability | ||
| B) | Scarcity of cocaine and poor cocaine quality | ||
| C) | New synthetic methods for cathinone production | ||
| D) | Legalization of cathinones for medical use |
Concurrently, the interception of cocaine shipments into Europe from South America made cocaine scarce and poor in quality. The European emergence of cathinones in the early to mid-2000s filled the void of MDMA and cocaine by promising users a legal-high substitute. Cathinones began replacing MDMA in Ecstasy and were introduced as over-the-counter "bath salt" products. The decreasing MDMA content in Ecstasy coincided with the 2009 emergence of cathinones in the United States, which were promoted as less expensive "legal high" ecstasy and cocaine alternatives [3].
| A) | It is the predominant marketplace for NPS | ||
| B) | It provides information on synthesis and use | ||
| C) | It connects manufacturers, suppliers, and users | ||
| D) | All of the above |
The Internet is the predominant marketplace for NPS and plays an essential role in the NPS phenomenon through a variety of mechanisms. NPS users and manufacturers are able to utilize the Internet for information on acquisition, synthesis, extraction, identification, and use of these substances. The Internet also serves as the marketplace that connects manufacturers, suppliers, retailers, and end users. It is increasingly common that manufacturers, suppliers, retailers, web-hosting, and payment processing services are based in different countries, and this decentralization of the online drug markets adds to the difficulty for law enforcement control [1,3,12].
| A) | It complicates the reversal of opioid overdoses with naloxone. | ||
| B) | It produces more intense euphoria. | ||
| C) | It has a lower risk of addiction. | ||
| D) | It is easier to manufacture. |
The growing issue of FAAX is of particular concern, as it complicates the reversal of opioid overdoses with naloxone and is responsible for widespread reports of injection site infections and necrosis resulting in amputations. Furthermore, people chronically exposed to FAAX often struggle with difficult withdrawal symptoms that may present unique treatment challenges compared to opioid withdrawal alone [16].
| A) | Tryptamine | ||
| B) | Phenethylamine | ||
| C) | Piperazine | ||
| D) | Aminoindane |
An astonishing diversity of structural families and subgroups of NPS and psychoactive drugs have been synthesized from the single parent molecule phenethylamine. Phenethylamines are a broad molecular class that can produce both hallucinogenic and stimulant effects. Phenethylamines fall into three sub-families: ring-substituted phenethylamines, amphetamines, and methylenedioxyphenethylamines. More than 180 phenethylamines have been reported to the UNODC, the majority of which are ring-substituted [1,8]. For the purposes of this course, phenethylamines (plural) refers to phenethylamine derivatives as a category.
| A) | By blocking GABA receptors | ||
| B) | By stimulating opioid receptors | ||
| C) | By antagonizing glutamate receptors | ||
| D) | By increasing synaptic monoamine levels |
All phenethylamines produce their stimulant, entactogenic, and/or hallucinogenic effects by increasing synaptic monoamine levels. Dopamine, serotonin (5-hydroxytryptamine or 5-HT), and norepinephrine are the monoamine neurotransmitters. Normally, dopamine, serotonin, or norepinephrine is released into the synaptic cleft, and then cleared from the synapse through uptake by their respective transporter. The last step involves vesicular monoamine transporter-2 (VMAT-2) located on the vesicular membrane. VMAT-2 uptakes the monoamines retrieved from the synapse and packages and stores them in synaptic vesicles for later release [1,8,10].
| A) | Synthetic cannabinoids are less potent | ||
| B) | Synthetic cannabinoids are not lipophilic | ||
| C) | Synthetic cannabinoids are full agonists at CB1 receptors | ||
| D) | Synthetic cannabinoids do not cause psychoactive effects |
THC and cannabimimetics bind and activate CB1 receptors to produce their euphoric effects. Compared to the partial CB1 agonist THC, full agonist cannabimimetics have greater potency, with toxicity and overdose potential uncharacteristic of cannabis. As a partial agonist, THC is limited in the extent it activates CB1 and shows a direct dose-response effect until a plateau is reached, with further dose escalation failing to increase drug effect. This partial agonist property contributes to the infrequent toxicity from cannabis use and the perception of cannabis as a "safe" drug. In contrast, the full CB1 agonist cannabimimetics do not possess a dose-response plateau and further use increases overdose and toxicity risk [45,46].
Cannabimimetics produce a substantially greater drug effect than THC, with CB1 receptor binding affinities 5 to 10,000 times greater and significantly higher dose-response efficacy. CB1 agonists inhibit GABAergic neurons that project to the nucleus accumbens, which disinhibits nucleus accumbens dopaminergic neurons that activate the mesolimbic dopaminergic pathways and contribute to the rewarding properties and abuse potential of cannabinoids. Because cannabimimetics more powerfully activate CB1, they produce more intense euphoria and reward. This greater inhibition of GABA-mediated neurotransmission also disrupts the balance of GABA/glutamate release in neuronal projections from the prefrontal cortex, which over-activates dopaminergic systems in the prefrontal cortex and striatum, inducing paranoia, agitation, anxiety, psychoses, and convulsions [18,45,46].
| A) | Tryptamines | ||
| B) | Naphthoylindoles | ||
| C) | Phenylacetylindoles | ||
| D) | Indole- and indazolecarboxamides |
The naphthoylindole sub-group of SCRA was independently synthesized by John W. Huffman (JWH-series) and Alexandros Makriyannis (AM-series) to identify the structural requirements for selective binding affinity to the CB1receptor. Despite a negligible selectivity for CB1, synthetic cannabinoids containing N-alkylated tail groups bearing four to six carbon atoms demonstrated effective hydrophobic interactions with the binding pocket of the receptor, leading to an increase in affinity, whereas shorter (or longer) N-alkyl groups decreased affinity significantly [1]. Replacement of the N-pentyl group, with either an N-5-fluoropentyl or N-5-cyanopentyl group, resulted in substantial increase in CB1 affinity. Chemical substitution of the ketone bridge with a methylene linker led to naphthylmethylindoles (e.g. JWH-175), which have a weaker affinity for the CB1 receptor compared to naphthoylindoles. However, modification of the 1-naphthyl head group, through the introduction of 4-alkoxy- (JWH-081) or 4-halo-substituents (JWH-398) provided access to active cannabimimetics. The most marked increase in potency was observed in 4-alkyl-substituted naphthoylindoles, which led to the JWH- and AM-series (specifically JWH-018 and AM-2201), which dominated the synthetic cannabinoid market for a period [1].
Simplified naphthoylindole derivatives, where the 1-napthyl group was replaced with either a phenylacetyl or benzoyl group were also developed to probe binding to the CB1 receptor. In the case of the phenylacetylindole (JWH-167) the affinity for the CB1-receptor was 10 times less than observed for JWH-018. However, the introduction of 2-alkyl- (JWH-251), 2-alkoxy- (JWH-250) or 2-halo-substituents (JWH-311, JWH203, and JWH-249), led to improved binding [1].
Substitution of the naphthalene group of JWH-018, with a 2-iodophenyl motif results in the benzoylindole derivative AM-679, which exhibits a similar level of binding to CB1 as JHW-018. As with the naphthoylindole family, subsequent replacement of the N-pentyl group, in the AM-679 with an N-5-fluoropentyl tail, resulted in a substantial increase in CB1 affinity (AM-694) [1].
The SCRA 3-acylindole derivatives, such as JWH-018 and AM-2201, emerged in globally in the late 2000s. They are characterized by non-aromatic, bulky alicyclic head groups, such as the adamantylindoles (e.g., AB-001) and tetramethylcyclopropylindoles (e.g., UR-144). As with the naphthoylindole series, the replacement of the N-pentyl group with an N-5-fluoropentyltail resulted in substantial increase in CB1 affinity and led to the emergence of cannabinoids such as 5F-AB-001 and XLR-11 [1].
Similar to the emergence of acylindoles, a variety of acylindazole SCRAs have also emerged. These substances, such as THJ-018, and THJ-2201, feature a modified indazole core but retain specific head and tail groups for optimal CB1 -receptor affinity [1].
In the early to mid-2010s, the NPS market pivoted toward SCRA analogs in which the acyl-linker was substituted by either an ester or an amide linker (e.g., indole-an indazole carboxylates, carboxamides). As with previous classes, affinity for CB1-receptor binding were retained [1].
In 2013, the first two indolecarboxylate SCRAs reported were the quinoline-8-yl derivatives, BB-22 (QUCHIC) and PB-22 (QUIPIC). Cannabimimetic binding of PB-22 was improved by sequential replacement of the quinoline-8-yl- group for a 1-naphthylgroup (CBL-018) and subsequent introduction of terminal fluorine into the N-pentyl tail, leading to a ten-fold increase in CB1 affinity (NM2201). Replacing the N-pentyl tail (in PB-22) with either an N-4-fluorobenzyl group or with an N-5-fluoropentyl chain resulted in FDU-PB-22, FUB-PB-22, and 5F-PB-22 [1].
Indazolecarboxylates are closely related to the indolecarboxylate family of cannabinoids, and some derivatives have been reported to UNODC, including the CBL-018, CBL-2201 analogs, SDB-005, 5F-SDB-005 25, quinoline-8-yl analogs, 5F-NPB-22 51, 52, FUB-NPB-22 53, adamantan-1-yl-1H-indazole-3-carboxylates: APINAC 54–57 and 5F-AKB-57 [1].
As a result of their inherent metabolic instability/toxicity, both the indoleand indazolecarboxylate families have been entirely replaced by the more stable amide (indole- and indazolecarboxamide) classes [1].
In 2012, APICA and its fluorinated derivative, 5F-APICA, became the first indolecarboxamide SCRAs in the NPS market, of which both exhibited moderate CB1 receptor affinity. As a result, a "mix and match" modification of the N-alkyl tails and replacement of the bulky adamantyl head group for either phenyl (N-phenyl-SDB-006), benzyl (SDB-006 and 5F-SDB-006), or 1-naphthyl(NNEI, 5F-NNEI; 5Cl-NNEI, and FDU-NNEI) groups led to a wide variety of products [1].
Phenyl- and benzyl-substituted indolecarboxamides generally exhibit weaker binding to the CB1 receptor compared to their adamantyl- and 1-naphthyl counterparts. The exception to this trend is the sub-family of (2-phenylpropan-2-yl)- (or cumyl-) CB1 agonists, which show significant increases in potency compared to their progenitors SDB-006 and 5F-SDB-006. Several 7-azaindole-3-car boxamide derivatives (also known as the 7AICA-series) have also emerged in the synthetic cannabinoid market, including 5F-AKB-48-7N, CUMYL-5F-P7AICA, CUMYL-4CN-B7AICA, and 5F-PCN [1].
Indazolecarboxamides are a direct extension of the indolecarboxamide family of cannabinoids, where the indole core is replaced with an indazole. Since 2012, various derivatives have been reported, for example SDB-005, 5F-SDB-005 (and analogs); MN-18, and 5F-MN-18. Other examples are the adamantan-1-yl-1H-indazole-3-carboxamides and cumyl-derivatives. These derivatives all show significant increases in cannabimimetic CB1 potency compared to their indole counterparts [1].
This is an important sub-family within the broader indole- and indazolecarboxamide series of synthetic cannabinoids, which include the valinamides (AB-series), tert-leucinamides (ADB-series), and/or phenylalaninamide (APP-series). The incorporation of esters like, methyl valinate (AMB- or MMB-series), ethyl valinate (AEB- or EMB-series), methyl tert-leucinate (MDMB-series), and/or ethyl tert-leucinate (EDMB-series) is also possible [1].
Unlike the previously discussed cannabimimetics, which are achiral, these SCRAs contain an asymmetric carbon. In theory, these compounds are present in two enantiomeric forms, dependent on the source and enantio-purity of the precursor chemicals used. In most cases, a higher potency at the CB1 receptor is observed for the (S)-enantiomer over the (R)-enantiomers. In seized samples, the more active enantiomer appears to predominate [1].
As with previous generations, the indole-valinamide synthetic cannabinoids with N-alkylated tail groups bearing 4 or 5 carbons exhibit nanomolar CB1 affinity (e.g., AB-PICA). Modification of the N-pentyl group, with either an N-5-fluoropentyl- (5F-AB-PICA) or aromatic N-4-fluorobenzyl- (AB-FUBICA), tail resulted in substantial increase in CB1 affinity. Compounds containing other side chains such as N-4-cyanobutyl (4CN-AB-BUTICA), N-cyclohexylmethyl (AB-CHMICA), and N-penten-4yl (AB-4en-PICA) have also been reported. Replacement of the indole core with an indazole (e.g., AB-PICA versus AB-PINACA) leads to a ten-fold increase in potency in each congeneric derivative. A similar increase in CB1-binding affinity was seen within the analogous indoleand indazole-tert-leucinamide [ADB-series] derivatives. The same was not observed in the APP-series derived from phenylalanidamide, where the presence of the bulky aromatic group significantly reduces CB1 cannabimimetic activity in many cases. Further chemical modification of the tail groups or replacement of the core with a 7-azaindole scaffold in the most active ADB-series resulted in an increase in the variety of potent and potentially more harmful analogs on the market [1].
An extension of this sub-family has also emerged, where the amino acid amide group was replaced with either a commercially available chiral methyl valinate (AMB- or MMB-series), ethyl valinate (AEB- or EMB-series), methyl tert-leucinate (MDMB-series), or ethyl tert-leucinate (EDMB-series) group. Similar to the AB-, ADB-, and APP-series, in most cases, a higher potency at the CB1 receptor is observed for the (S)-enantiomer over the (R)-enantiomers. The AMB-/MMB- and MDMB-series of derivatives bearing N-4-fluoropentyl, N-5-fluoropentyl and N-penten-4-ylgroups show the same trends, except for in terms of binding affinity as their amide counterparts with indazoles observed to be more potent than indoles and the tert-leucinate derivatives more potent than the valinate derivatives [1].
The N-4-fluorobenzyl-, N-cyclohexylmethyl-, N-4-cyanobutyl-, N-5-chloropentyl-, and 7-azaindole derivatives show similar trends in terms of their CB1 -binding affinities as their corresponding amide counterparts. A small number of ethyl valinate (EMB-) and tert-leucinate (EDMB-) derivatives have also been reported [1].
After the national control of some indoles, indazole, and benzimidazole-derived synthetic cannabinoids, the NPS market again shifted towards previously unexplored chemical structures. In 2014, tricyclic synthetic cannabinoids, such as the carbazole and γ-carboline were first identified and exhibited moderate CB1 affinity. Between 2017 and 2020 several γ-carboline analogs have emerged in which the N-pentyl tail has been replaced with either a N-5-halopentyl or cycloalkyl group [1].
In 2021, new substances with previously unencountered and/or not well-characterized structural modifications appeared on the market, including the weak CB1 binding N-alkylisatin-acylhydrazone, MDA-19 (also known as BZO-HEXOXIZID), and its related analogs [1]
| A) | Psychosis | ||
| B) | Sedation | ||
| C) | Hypothermia | ||
| D) | Respiratory depression |
Natural cannabis and cannabimimetics overlap mechanistically through CB1 receptor binding and activation to produce the shared subjective effects of relaxation, euphoria, perceptual changes (e.g., altered sense of time, intensified sensory experiences), cognitive impairment (e.g., amnestic symptoms, slowed reaction time), and the physiologic effects of xerostomia, conjunctival injection, and tachycardia. Acute changes in mood, anxiety, perception, thinking, memory, and attention are common to both. Agitation, aggression, paranoia, anxiety, and psychoses are common with cannabimimetic use and less common or rare with cannabis use. As discussed, the more frequent and severe psychosis, agitation, and sympathomimetic effects with cannabimimetic use reflect greater potency, full CB1 agonist action, and absence of CBD [1,8,45].
| A) | 2C-series | ||
| B) | NBOMe compounds | ||
| C) | Benzofurans | ||
| D) | Piperazines |
As noted, phenethylamines are a class of NPS that can have stimulant and/or hallucinogenic effects depending on the position and identity of functional group substituents on the phenethylamine core. More than 180 individual phenethylamine NPS have been reported to the UNODC, 80 of which are hallucinogenic. Among the reported hallucinogenic phenethylamines, 80% possess a 2,5-dimethoxy substitution pattern on the aromatic ring, characteristic of "classic hallucinogens."
The classic hallucinogens within the phenethylamines are represented by the 2C-series and NBOMe analogs, and the 2D-series. Addition of methoxy-groups at the 2 and 5 positions of phenethylamine, with any hydrophobic substitution at the 4 position, confers hallucinogenic activity and produces the 2C-series. Adding a 2-methoxybenzyl (MeOB) unit onto the nitrogen molecule of 2C drugs confers substantially greater potency and forms the NBOMe series. The hallucinogenic properties of 2C drugs are further enhanced by introducing a methyl-group at the alpha-carbon, providing access to ring-substituted amphetamine derivatives, known as D-series hallucinogens. All ring-substituted phenethylamines are potent serotonin (5-HT2A) receptor agonists, and many have strong activity in other receptor complexes [1].
Additional hallucinogens, or the remaining 20% not considered "classic hallucinogens," are compounds containing the 2,5-dimethoxy substitution, -3,5-dimethoxy substitution, and trimethoxy substitution, or are NBOMe variations of amphetamines, mescaline analogues, and the "Fly" compounds (benzofurans and benzodifurans) [1].
The 2C-series sub-group is the largest of the three hallucinogenic phenethylamines. The powerful hallucinogen 2C-B was the first 2C synthesized, in 1974, by simple alterations to the natural phenylethylamine molecule mescaline. The more commonly encountered 2Cs in the United States are 2C-B and 2C-T-7, known by the street names Nexus, Bromo, Blue Mystic, and T7 [1,15].
The effect following oral use in the lower dose range (<8 mg for 2C-B and 10–50 mg for 2C-T-7) lasts six to eight hours and is often described as relaxation, awareness of integration between sensory perception and emotional state, and euphoria with increased body awareness and enhanced receptiveness of visual, auditory, olfactory, and tactile sensation. Dosing in the upper limits results in greater stimulant effects and a state of substantially greater intoxication. Even higher dosing produces LSD-like visual and auditory effects and potentially extremely fearful hallucinations and morbid delusions. User reports of 2C drug effects describe a blend of MDMA-like empathy and entactogenic effects with LSD-like psychedelic effects. 2C-B is used primarily as a club drug in the rave culture and circuit party scene, where some users ingest 2C-B in combination with LSD (a "banana split") or MDMA (a "party pack"). Several fatalities have been reported from co-ingestion of 2C-T-7 and MDMA [51,53].
Possible adverse effects include nausea, vomiting, agitation, tachycardia, hypertension, respiratory depression, seizures, psychosis, and suicidal thoughts. Excited delirium with agitation and violent behavior, hyperactivity, hyperthermia, and cardiopulmonary arrest have been documented following 2C use. Immediate action is required with excited delirium, hyperthermia, and seizure activity, because presence of vomiting, agitated behavior, and seizures are risk factors for fatal 2C toxicity [1,18].
The introduction of a methyl-group in the alpha position of 2C-series substances provides access to ring-substituted amphetamine derivatives, known as the D-series. Included are 4-iodo-2,5-dimethoxyamphetamine (DOI) and the trimethoxyamphetamines (TMA-2 and TMA-6). Compared with the 2C-series, D-series substances are metabolically stable to monoamine oxidases in the body, making them significantly more potent with a duration of action up to three times greater (6 to 10 hours versus 16 to 30). Reported adverse effects associated with the use of D-series derivatives include agitation, tachycardia, mydriasis, hallucinations, severe limb ischemia, seizures, liver and renal failure [1,8].
The N-benzylphenethylamines (NBOMe) series was first developed in the early to mid-2000s for the purpose of researching mammalian serotonin receptor distribution. Initial Internet discussion and law enforcement attention both occurred in 2010. They are commonly known by the street names N-Bomb, Smiles, 25I, 25C, and 25B [32].
As noted, the NBOMes are synthesized from 2C phenethylamines by the addition of a 2-methoxybenzyl (MeOB) unit onto the nitrogen molecule. This molecular appendage confers greater potency than its 2C counterpart; for example, the dose of 2C-I is roughly 20 mg versus 50–100 mcg with 25I-NBOMe. The hallucinogenic effects are mediated by highly potent and selective agonist activity at 5-HT2A receptors [1,32].
The NBOMe series is sold as powder, liquid solution, or soaked into blotter paper. NBOMe appears in products sold as LSD, a widespread counterfeiting practice that is encouraged by the cheaper cost of NBOMe. This poses a potentially serious health risk to the user, who instead of ingesting the physiologically benign LSD, unsuspectingly ingests NBOMe and risks potentially severe and fatal adverse effects [33].
The effects of NBOMe last 6 to 10 hours with sublingual ingestion. Users report desired effects of euphoria, mental/physical stimulation, feelings of love/empathy, altered consciousness, and unusual body sensations. Negative effects include confusion, shaking, nausea, insomnia, paranoia, and intense negative emotions. Users with severe NBOMe toxicity show violent, severely agitated, and hallucinating presentations and require hospitalization, as hyperthermia, tachycardia, hypertension, seizures, metabolic acidosis, elevated creatine kinase, and acute renal injury are usually present. Even small amounts can cause seizures, cardiac and respiratory arrest, and death. Many fatalities have occurred following NBOMe use, typically preceded by excited delirium [1,32].
Benzofurans include 1-(benzofuran-5-yl)-propan-2-amine (5-APB), 6-APB, and their dihydro-derivatives 5-APDB and 6-APDB. Benzofurans are analogs of MDMA and MDA, first synthesized in the 1990s at Purdue University for researching structure-activity relationships of MDMA-like molecules. In 2010, 5/6-APB entered the UK market as an MDMA replacement "legal high" under the brand name Benzofury (derived from benzofuran) and became very popular. Other benzofurans include IAP and 5-APDI, which replace both oxygen atoms of MDA with methylene groups; 5- and 6-API, which replace the oxygen atom in the heterocyclic rings of 5/6-APB with a nitrogen atom; and 5-MAPB, an N-methyl analog of 5-APB [1,8,15].
Benzofurans are dopamine, norepinephrine, and serotonin inhibitors, with greatest potency at dopamine and norepinephrine receptors. As full 5-HT2B agonists, 5/6-APB may be cardiotoxic with long-term use. User reports describe an empathogenic and stimulant effect, with 5-APB more potent than 6-APB. Several fatalities have been attributed to benzofurans, with hyperpyrexia noted in several cases. Emergency department admissions for benzofuran toxicity have noted tachycardia, elevated blood pressure, and fever [1,8].
Benzodifurans are termed the "fly" drugs in reference to their insect-resembling molecular structure. They include tetrahydrobenzodifuranyl (Fly), 2C-B-Fly, 3C-B-Fly, and the most potent and widely used drug of this category, benzodifuranyl aminoalkane (Bromo-Dragonfly or B-Fly). The phenyl ring bound between two dihydrofuran rings in B-Fly produces much greater potency and duration of action than most phenethylamine derivatives. B-Fly mechanism of action is mediated primarily by agonist activity at 5-HT2A receptors and, to some degree, 5-HT1 and 5-HT2C receptors [1,8,15].
Recreational use of B-Fly was first noted in 2001 and became widespread in 2008, primarily through Internet mediation [63]. B-Fly is sold for oral use in blotter paper or liquid. Following a typical 200–800 mcg dose, the onset of effects can take six hours. Many users assume the initial dose ineffective and ingest another dose or other substances. The drug effect commonly lasts two to three days and is described as profound hallucinations (mainly visual, with geometric patterns and lights), sound alterations, a sense of connection/belonging with other realities, a sense of peace and well-being, emotional stimulation, and meeting with metaphysical entities. Commonly reported adverse effects include nausea and vomiting, headache, tachycardia, elevated blood pressure, lung collapse, gastrointestinal disturbances, muscle tension, tremor, anxiety, panic attacks, arrhythmias, heart murmurs, convulsions, flashbacks, memory disturbances, confusion, and paranoid ideation. Several fatalities have been reported in Europe, but attribution is unclear, as polysubstance use (particularly with ketamine) is common with B-Fly [1,8,15].
| A) | Tryptamines primarily affect serotonin systems | ||
| B) | Tryptamines have higher abuse liability | ||
| C) | Tryptamines are more likely to cause neurotoxicity | ||
| D) | Tryptamines have longer duration of action |
Tryptamines are monoamine alkaloids synthesized by decarboxylation of tryptophan and are quite varied. They include natural neurotransmitters (e.g., serotonin, melatonin); hallucinogens found in plants, fungi, and animals (dimethyltryptamine [DMT], 5-MeO-DMT, bufotenin); synthetic pharmaceutical products (e.g., sumatriptan and zolmitriptan to treat migraine); and various synthetic hallucinogenic compounds, such as alpha-methyltryptamine (AMT), diisopropyltryptamine (DiPT), 5-MeO-DiPT, 5-MeO-AMT, diethyltryptamine (DET), and 5-MeO-DET [1; 8]. Use of tryptamines for psychoactive effect began in the late 1950s with psilocybin, the natural ingredient in certain mushroom species. Synthetic tryptamines appeared on the illicit drug market in the United States during the 1990s .
More than 60 individual tryptamine NPS have been reported to the UNODC. Tryptamines have an indole ring structure (a fused pyrrole and benzene double-ring) joined to an amino group by a 2-carbon side chain. Psychoactive effects are closely related to their structural influence on receptor affinity. Tryptamines produce dominant hallucinogenic/psychedelic effects as 5-HT2A/1A/2C receptor agonists. Alpha methylation leads to stimulant activity, as with AMT and 5-MeO-AMT. Many synthetic tryptamines are monoamine releasers, increasing the risks of serotonin syndrome and sympathomimetic toxicity. With primarily serotonergic action, tryptamines lack reinforcement and abuse liability. NPA tryptamines are grouped by structure into three categories: indole ring-unsubstituted tryptamines, 4-position ring-substituted tryptamines (e.g., psilocybin), and 5-position ring-substituted tryptamines.
| A) | Mitragynine | ||
| B) | Salvinorin A | ||
| C) | Ibogaine | ||
| D) | Mescaline |
Mitragynine is the primary active alkaloid of kratom. Kratom leaves are ingested by chewing or boiling into tea. The effects last two to five hours. Low doses produce increased alertness, physical energy, talkativeness, and sociable behavior. High doses produce an opioid-like effect with sedation and euphoria. Undesired effects include nausea, itching, sweating, dry mouth, constipation, increased urination, and loss of appetite [49].
| A) | Delirium | ||
| B) | Bradycardia | ||
| C) | Rhabdomyolysis | ||
| D) | Sympathetic hyperarousal |
Excited delirium syndrome, also referred to more recently as agitated delirium, is the most serious NPS-induced toxicity, is a severe, life-threatening state of agitated delirium and autonomic dysregulation. This syndrome is characterized by sympathetic hyperarousal (e.g., hyperthermia, vital sign abnormalities, metabolic acidosis), delirium (altered consciousness with diminished awareness of one's environment), rhabdomyolysis, and agitated or violent behavior. Patients with excited delirium are incoherent and combative; emergency department arrival is often by EMS transport or police escort in physical restraints. Many sustain traumatic injuries before first responder contact and intensely struggle even when struggle is futile, resulting in self-harm. Some patients may strip naked, reflecting the combined hyperthermia and altered mental status [28,58].
| A) | They are more widely available | ||
| B) | They have a wider safety margin | ||
| C) | They do not interfere with dopaminergic function | ||
| D) | They are more effective at reducing fever |
The ability of EMS or emergency department staff to safely subdue patients with excited delirium has been elusive. Delays in medical treatment and the use of conventional restraints can be fatal. The behavioral symptoms of excited delirium impose a serious safety hazard to EMS, emergency department staff, and the patient. TASER and physical restraints are standard control measures but produce further destruction of muscle tissue, exacerbating the risks of subsequent renal failure and cardiopulmonary collapse. Benzodiazepines and haloperidol are used by some EMS to calm patients with excited delirium before attempting emergency transport. In this setting, IV administration is usually impossible, intramuscular administration delays the onset, and the dose required to sedate violent patients risks adverse hemodynamic and respiratory complications. Antipsychotic drugs interfere with already-compromised dopamine function [30].
| A) | Presence of hyperthermia | ||
| B) | Tachycardia | ||
| C) | Violent agitation | ||
| D) | Hypertension |
Sympathomimetic toxidrome resembles excited delirium, differing by dominant hyperadrenergic symptoms of tachycardia, hypertension, nausea/vomiting, and diaphoresis and a lack of violent agitation. Excited delirium syndrome and sympathomimetic toxidrome can co-occur. The presumed underlying hyperdopaminergic and hyperadrenergic states of excited delirium and sympathomimetic toxidrome, respectively, are intertwined. As such, co-occurrence in NPS toxicity is probably frequent, and management is highly similar [15,18].
| A) | Myoclonus | ||
| B) | Hyporeflexia | ||
| C) | Diaphoresis | ||
| D) | Hyperthermia |
Serotonin syndrome is a state of excess serotonin activity from serotonergic agent overdose or synergistic toxicity. Serotonin syndrome shares some features with excited delirium and sympathomimetic toxidrome, but patients are rarely aggressive and violent. Patients typically present with psychomotor agitation, and cognitive (e.g., confusion, delirium), neuromuscular (e.g., akathisia, ataxia, myoclonus, hyper-reflexia), and autonomic (e.g., dizziness, nausea/vomiting, tachycardia, sweating) symptoms. It can be differentiated from sympathomimetic toxidrome by the presence of shivering, rigidity, myoclonus, and hyper-reflexia. Serotonin syndrome is characterized by a rapid onset of neuromuscular symptoms with markedly increased muscle tone, along with shivering, tremors, hyper-reflexia, akathisia, ataxia, and myoclonus. Sweating may decrease and contraction of opposing muscle groups generates heat more rapidly than vasodilatation, leading to hyperpyrexia and cardiovascular instability. The mortality rate is 10% to 15% [8,15].
| A) | Immediate intubation | ||
| B) | Administering activated charcoal | ||
| C) | Administration of antipsychotics | ||
| D) | Rapid, aggressive sedation with benzodiazepines |
If treatment of excited delirium or sympathomimetic toxidrome is neglected, delayed, or inadequate, the outcome is often multiple end-organ damage or death. The most essential aspect of the management of cathinone toxicity is rapid, aggressive sedation with benzodiazepines. Benzodiazepines are the agents of choice because they decrease excessive heart rate, blood pressure, neural stimulation, and muscular activity; prevent seizures; protect against physical violence; and reduce muscular hyperactivity that drives fever, rhabdomyolysis, and renal failure. Benzodiazepines have a wide safety margin and, contrary to common belief, do not dangerously decrease cardiovascular or respiratory parameters unless used with potent sedatives. Immediate calming may require IM lorazepam, midazolam, or ketamine to allow for safe placement of IV access. With access in place, IV diazepam may be initiated, the preferred agent for effective rapid titration because full onset of each dose occurs within five minutes, allowing repeat dosing without the "overshooting" risk with slower-onset lorazepam. Patients may require very high doses for effective sedation. Propofol or barbiturates in those appearing refractory to high-dose benzodiazepine [18,28,30]. Antipsychotic drugs interfere with already-compromised systemic dopaminergic function and should be avoided in patients with suspected excited delirium.
| A) | Increased pain sensitivity | ||
| B) | Tolerance and dependence | ||
| C) | Withdrawal syndrome upon cessation | ||
| D) | All of the above |
The abuse potential of synthetic cathinones and other opioid receptor agonists can be predicted by pharmacologic activity. The ratio of dopamine to serotonin influences episodic (i.e., recreational) versus compulsive (i.e., addictive) use patterns. Cathinones release more dopamine than serotonin (similar to methamphetamine and cocaine), which predicts drug craving, urge to re-dose, and addiction liability. Drugs that release higher serotonin than dopamine levels (e.g., MDMA) tend to have a dampening effect on craving and urge to re-dose and a lower abuse potential [1,58]. Frequent high-dose opioid use induces tolerance, dependence, craving, and a withdrawal syndrome with cessation characterized by depression, anxiety, sleep disorders, and fatigue, with craving, anhedonia, and anergia that can last several weeks. Class-wide, withdrawal symptoms include depression, impulsivity, anhedonia, and cognitive complaints of poor concentration and attention [18].
| A) | Confrontational interventions | ||
| B) | Motivational interviewing | ||
| C) | Mandatory treatment programs | ||
| D) | Punitive measures |
Because patients with problematic NPS use may be ambivalent about changing behavior, clinicians should demonstrate respect for patient autonomy by expressing empathy without confrontation. Providing appropriate, accurate information on the relative risks and unknown harms of NPS empowers patients in making informed decisions to continue NPS use, attempt to quit, or seek treatment [50].
In the primary care setting, patients with NPS-related problems may present with concerns over their NPS use or with problems they suspect are NPS-related. Alternatively, patients may describe an NPS-related problem without linking it to NPS use. Motivational interviewing is suggested because this technique is proven useful in resolving patient ambivalence over change with numerous clinical conditions. This approach involves first appreciating and addressing patient concerns and withholding advice until greater clarity emerges. This empowers active patient participation and facilitates positive behavioral change. To begin this process, gain patient permission before questioning about substance use. If granted, mention confidentiality. If concern is from a family member, explore further, ask about their coping, and provide info on relevant support if needed [50]. With assessment of patients acknowledging drug use-related problems, invite active patient contribution by asking open-ended questions, such as:
"Tell me about your drug use."
"What is your drug use during an average week?"
"What concerns do you have?"
"You mentioned discomfort when urinating—how might that be related to your drug use?" (e.g., ketamine abuse associated with urinary complications)
To help build rapport, ask about drug jargon and drug effects. Giving feedback with specific reference to patient concerns can help patients re-frame their drug use and consequences.
After the basic situation and clinical picture has been established, the next steps should be determined. Further questions may include:
"Where would you like to go with this next?"
"Is there anything I can specifically help with?"
This can involve further information about the presenting problem or drug use, harm-reduction advice, guidance on managing physical or psychiatric problems, exploration of abstinence, or specialist referral.
Patients who clearly link drug use with a problem are likely to ask questions and be receptive to expert input. Apply a circular process to engage patient interest:
"Would you like to know some more about how MDPV can affect your mood?"
"When people use stimulants over a weekend and don't get any sleep, it can reduce chemicals in the brain that help keep our mood stable and feeling happy."
"How does that fit with your experience?"
Avoid assuming the patient wants to change or needs expert help to change. Instead, introduce the concept of change by asking:
"We've discussed some concerns you have, and how they might be related to your drug use. Where do we go from here?"
"Would you like to do something about your drug use?"
If a patient expresses the wish to change, ask how he or she might do this and whether professional support is needed. In patients unsure about what they should do, consider harm-reduction advice. As little is known about NPS, give general harm reduction advice such as limiting use, a period of cessation to observe improvement in health concerns, and total avoidance in high-risk patients (e.g., those with a history of psychiatric illness, addiction). The appointment should end with permission to revisit the subject in the future [50].
| A) | Condemnation of all drug use | ||
| B) | Abstinence-only education | ||
| C) | Recognizing that some risks can be mitigated | ||
| D) | Encouraging safer alternative drugs |
Harm reduction neither condones nor condemns drug use, but instead recognizes that some risks from recreational NPS use can be mitigated. DanceSafe is the largest harm-reduction organization for North American nightlife/electronic dance music communities. Efforts by DanceSafe are directed at non-addicted recreational users, who comprise the largest number of drug users but are underserved by conventional harm reduction that targets addicted users. DanceSafe objectives include reducing drug misuse and empowering users to make informed decisions about their health and safety by providing unbiased educational literature on the effects/risks of specific drugs; remote and, when possible, on-site adulterant screening (drug testing); on-site free water and electrolytes to help prevent hyperthermia; free ear plugs; free safe sex tools to avoid pregnancy and sexually transmitted infections; and first point of contact for adverse drug effects [52]. Many other American and European harm-reduction groups use common objectives and methods.